Treating Anemic Patients With Myelofibrosis in the New Janus Kinase Inhibitor Era: Current Evidence and Real-world Implications
Authors: Aaron T. Gerds, Prithviraj Bose, Gabriela S. Hobbs, Andrew T. Kuykendall, Lynn M. Neilson, Jinlin Song, Barbara Klencke, Claire N. Harrison
Journal: HemaSphere (2022)

Anemia is a prevalent and burdensome clinical manifestation of myelofibrosis (MF) with a complex etiology. Most MF patients are anemic within 1 year of diagnosis, and nearly all become dependent on red blood cell transfusions over time.1 Anemia is associated with a reduced health-related quality of life (HRQoL) and shortened survival.2 Moreover, anemia and transfusion dependence are independent negative prognostic indicators incorporated into standard clinical MF risk scoring systems.3 While specific subsets of patients with MF may derive temporary anemia benefit from androgens (eg, danazol), corticosteroids (eg, prednisone), immunomodulators (eg, pomalidomide), or erythropoiesis-stimulating agents, the vast majority of patients will not achieve a prolonged response.2 The Janus kinase inhibitor (JAKi) ruxolitinib has been a decade-long standard of care for patients with intermediate- and high-risk MF due to its efficacy in reducing spleen size and improving disease-related symptoms; however, ruxolitinib is myelosuppressive and associated with dose-dependent worsening of anemia.4 More recently, the JAKi fedratinib and pacritinib have each been approved for the treatment of MF, having demonstrated spleen and symptom improvements compared with placebo or best available therapy.5,6 Like ruxolitinib, new-onset or worsening anemia is commonly reported with fedratinib treatment,5 whereas pacritinib is relatively nonmyelosuppressive.6 Notably, the investigational agent momelotinib is the first and only JAKi to also target the iron regulator activin A receptor type 1/activin receptor-like kinase-2 (ACVR1/ALK2), addressing the unmet need of anemia in MF patients in addition to the traditional treatment goals of JAK inhibition: reducing splenomegaly and symptom burden.2 Due to the lack of comparative information among these expanding treatment options, a systematic literature review and network meta-analysis (NMA) of 7 randomized controlled trials of JAKi in patients with MF (noted in Table 1) by Sureau et al evaluated the relative efficacy and tolerability of treatments, including endpoints of reduced spleen volume and adverse events due to hematologic toxicity, among others.7 This NMA demonstrated that ruxolitinib, momelotinib, and fedratinib were comparably efficacious in reducing spleen volume (with ruxolitinib and momelotinib providing significant improvements in achieving ≥35% spleen volume reduction at 24 weeks compared with pacritinib), while momelotinib was associated with significantly less grade 3/4 anemia compared with ruxolitinib, fedratinib, or pacritinib.7 However, this analysis did not include real-world studies, examine anemia-related benefits among treatments (such as decreased transfusion need), or evaluate the differential impact of therapies on the HRQoL and economic burden associated with anemia and transfusions in MF. Table 1 - Summary of the Impact of JAKi and Imetelstat on Transfusion Burden in Clinical and Real-world Studies of MF Treatment Publication Trial name/Data Source Number of Patients Anemia Rate Impact on Transfusion Burden Measurement Results Measurement Results Overall Change in %TI Patients From BL to W24 or End of Treatment Phase 3 clinical trials Ruxolitinib Verstovsek et al. N Engl J Med. 2012;366:799–807. COMFORT-1* Ruxolitinib (n = 155)Placebo (n = 154) Proportion of patients with grade 3 anemia during month 0–6 26.4% (ruxolitinib)10.7% (placebo) Proportion of patients who were TD at baseline who achieved TI during the study 41.2% (ruxolitinib) vs 46.9% (placebo) P = NR NR Proportion of patients with grade 4 anemia during month 0–6 11.5% (ruxolitinib)3.1% (placebo) Harrison et al. N Engl J Med. 2012;366:787–798. COMFORT-2* Ruxolitinib (n = 146)BAT (n = 73) Exposure-adjusted rate (event per 100 patient-years) of grade 3/4 anemia 21 (12.3) (ruxolitinib)5 (7.5) (BAT) Proportion of patients who received ≥1 RBC transfusion during the treatment period 51% (ruxolitinib) vs 38% (BAT) P = NR NR Al-Ali et al. haematologica 2016; 101:1065. JUMP Ruxolitinib (n = 1144) Proportion of patients with grade 3/4 anemia 33.0% NR NR NR Fedratinib Pardanani et al. JAMA Oncol. 2015;1:643–651. JAKARTA-1* Fedratinib 400 mg daily (n = 96)Fedratinib 500 mg daily(n = 97)Placebo (n = 96) Proportion of patients with grade 3/4 anemia 43% (fedratinib 400 mg)60% (fedratinib 500 mg)25% (placebo) Proportion of patients who were TD at baseline who achieved TI during follow-up 92.3% (fedratinib 400 mg and 500 mg pooled) vs 50% (placebo) P = NR –9% Pacritinib Mesa et al. Lancet Haematol. 2017;4:e225–e236. PERSIST-1* Pacritinib 400 mg (n = 220)BAT excluding JAKi (n = 107) Proportion of patients with grade 3/4 anemia through W24 17% (pacritinib 400 mg)15% (BAT) Proportion of patients who were TD at baseline who achieved TI during follow-up 25% (pacritinib 400 mg) vs 0% (BAT) P = 0.043 NR Mascarenhas et al. JAMA Oncol. 2018;4:652–659. PERSIST-2* Pacritinib 400 mg once daily (n = 75†)Pacritinib 200 mg twice daily (n = 74†)BAT (n = 72†) Proportion of patients with grade 3/4 anemia 27% (pacritinib 400 mg)22% (pacritinib 200 mg)14% (placebo) Proportion of patients not TI at baseline who had reduced transfusion burden at W24 20.5% (pacritinib 200 mg and 400 mg pooled) vs 8.6 (BAT) P = NR +1.3% (pacritinib 400 mg)+1.4% (pacritinib 200 mg)0% change (placebo) Momelotinib Mesa et al. J Clin Oncol. 2017;35:3844–3850. SIMPLIFY-1* Momelotinib (n = 215)Ruxolitinib (n = 217) Proportion of patients with grade 3/4 treatment-emergent anemia 5.6% (momelotinib)23.1% (ruxolitinib) Proportion of patients who were TI at W24 66.5% (momelotinib) vs 49.3% (ruxolitinib) P < 0.001 –2% (momelotinib)–21% (ruxolitinib) Proportion of patients who were TD at W24 30.2% (momelotinib) vs 40.1% (ruxolitinib) P = 0.019 Median rate of transfusion (units/month) 0 (momelotinib) vs 0.4 (ruxolitinib) P < 0.001 Harrison et al. Lancet Haematol. 2018;5:e73–e81. SIMPLIFY-2* Momelotinib (n = 104)BAT (n = 52) Proportion of patients with grade 3/4 treatment-emergent anemia 13.5% (momelotinib)13.5% (BAT) Proportion of patients who were TI at W24 43% (momelotinib) vs 21% (BAT) P = 0.0012 +12% (momelotinib)–16% (BAT) Phase 2 clinical trials Ruxolitinib Mead et al. Br J haematol. 2015;170:29–39. ROBUST Ruxolitinib (n = 48) Proportion of patients with grade 3/4 anemia 20.8% Proportion of patients who were TD at baseline achieved TI by the end of the study 17% (1 out of 6 evaluable patients) NR Talpaz et al. J Hematol Oncol. 2018;11:1–0. NCT01445769 Ruxolitinib (n = 45) Proportion of patients with grade 3/4 treatment- emergent anemia 20.0% Proportion of patients who were TI 66.7% (baseline)53.3% (by the end of treatment phase) -13% Talpaz et al. J Hematol Oncol. 2013;6:1–0. NCT01348490 Ruxolitinib (n = 50) Proportion of patients with grade 3/4 anemia 42.2% Proportion of patients who required RBC transfusion 40.0% (in 12 W before baseline)60.0% (during the treatment phase of the study) NR Ruxolitinib + lenalidomide Daver et al. Haematologica. 2015;100:1058. NCT01375140 Ruxolitinib and lenalidomide (n = 31) NR NR NR NR NR Fedratinib Harrison et al. Am J Hematol. 2020;95:594–603. JAKARTA-2 Fedratinib 400 mg (n = 97) Proportion of patients with grade 3/4 treatment- emergent anemia 38% Proportion of patients who had treatment-emergent TD 8% NR Pacritinib Gerds et al. Blood adv. 2020;4:5825–35. PACIFICA Pacritinib 100 mg QD(n = 52)Pacritinib 100 mg BID (n = 55)Pacritinib 200 mg BID (n = 54) Proportion of patients with grade 3/4 anemia 9.6% (pacritinib 100 mgQD)7.3% (pacritinib 100 mg BID)20.4% (pacritinib 200 mg BID) Proportion of patients with reduction in transfusion burden by 50% or greater 17.9% (pacritinib 100mgQD)35.5% (pacritinib 100 mg BID)14.7% (pacritinib 200 mg BID) NR Momelotinib Oh et al. Blood adv. 2020;4:4282–91. NCT02515630 Momelotinib (n = 41) Proportion of patients with grade 3 or above anemia 12% Proportion of patients achieved TI by W24 34% +34% Imetelstat Tefferi et al. N Engl J Med. 2015 Sep 3;373:908–19. NCT01731951 Imetelstat (n = 33) Proportion of patients with grade 3/4 treatment- emergent anemia 30% Proportion of patients who TD and who achieved TI 31% (4/13) NR Real-world studies NR‡ Masarova et al. Eur J haematol. 2018;100:257–63. University of Texas MD Anderson Cancer Center Overall (n = 1,269)Patients with platelet count > 100 × 109/L (n = 948)Patients with platelet count 50–100 × 109/L (n = 178)Patients with platelet count < 50 × 109/L (n = 145) Proportion of patients with anemia (hemoglobin < 10 g/dL) at baseline 43% (overall)38% (patients with platelet count > 100 × 109/L)52% (patients with platelet count 50–100 × 109/L)68% (patients with platelet count < 50 × 109/L) Proportion of patients with TD at baseline 26% (overall)18% (patients with platelet count > 100 × 109/L)38% (patients with platelet count 50–100 × 109/L)62% (patients with platelet count < 50 × 109/L) NR NR‡ Masarova et al. Leuk Res. 2017;59:110–6. University of Texas MD Anderson Cancer Center PMF (n = 755)PET/MF(N = 163)PPV/MF (N = 181) Proportion of patients with anemia (hemoglobin < 10 g/dL) at baseline 43% (PMF)38%(PET/MF)41% (PPV/MF) Proportion of patients with TD at baseline 29% (PMF)17%(PET/MF)20% (PPV/MF) NR NR‡ Naqvi et al. Leuk Lymphoma. 2017;58:866–71. University of Texas MD Anderson Cancer Center PMF (n = 24)PET/MF (N = 4)PPV/MF (N = 7) NR NR NR NR NR All patients treated with ruxolitinib Kuykendall et al. Ann hematol. 2018;97:435–41. Lee Moffitt Cancer Center 64 Proportion of patients with anemia (hemoglobin < 10 g/dL) prior to ruxolitinib 51% NR NR NR Proportion of patients with anemia (hemoglobin < 10 g/dL) post ruxolitinib 70% NR‡ Kuykendall et al. Clin Lymphoma Myeloma Leuk. 2017;17:e45–53. Lee Moffitt Cancer Center 309 Proportion of patients with anemia OR TD at baseline 55% Proportion of patients with anemia OR TD at baseline 55% NR All patients treated with ruxolitinib Gerds et al. ASCO Ann meeting. 2020; e19539–e19539. Chart review 104 NR NR NR NR NR NR‡ Vallapureddy et al. Blood Cancer J. 2019;9:1–8. Mayo Clinic 1,306 Proportion of patients with moderate/severe anemia at first referral 54% Proportion of patients with TD at first referral 32% NR NR‡ Szuber et al. Am J Hematol. 2018;93:1474–84 Mayo Clinic PMF, age ≤ 40(n = 63)PMF, age 41–60 (n = 388)PMF, age >60 (n = 831) Proportion of patients with anemia (hemoglobin < 10 g/dL) at first referral 47% (all PMFpatients)23% (PMF, age ≤ 40)37% (PMF, age 41–60)54% (PMF, age >60) Proportion of patients with TD at first referral 13% (PMF,age ≤ 40)24% (PMF, age 41–60)38% (PMF, age >60) NR NR‡ Pardanani et al. Am J Hematol. 2013;88:312–6. Mayo Clinic 203 Proportion of patients with anemia (hemoglobin < 10 g/dL) at first referral 59% Proportion of patients with TD at first referral 38% NR NR‡ Tefferi et al. Mayo Clin Proc. 2012;Vol. 87, No. 1, pp. 25–33 Mayo Clinic 1,000 Proportion of patients with anemia (hemoglobin < 10 g/dL) at first referral 54% Proportion of patients with TD at first referral 38% NR All patients treated with ruxolitinib Mascarenhas et al. J Med Econ. 2020;23:721–7. Optum, MarketScan, and SEER 290 Proportion of patients with anemia 36% (30 days after ruxolitinib initiation)53% (60 days after ruxolitinib initiation)60% (90 days after ruxolitinib initiation)66% (180 days after ruxolitinib initiation)53% (30 days after ruxolitinib discontinuation)65% (60 days after ruxolitinibdiscontinuation)69% (90 days after ruxolitinib discontinuation)77% (180 days after ruxolitinib discontinuation) NR NR NR NR‡ Vekeman et al. Leuk Lymphoma. 2015;56:2803–11. MarketScan and IMS PharMetrics TD patients with iron chelation therapy (n = 103)TD patients with iron chelation therapy (n = 468) Proportion of patients with anemia 86.4% (TD patients with iron chelation therapy)77.4% (TD patients with iron chelation therapy) Months from first MF diagnosis to TD, median (range): 2.9 (0.03, 33.80) (TD patients with iron chelation therapy)4.3 (0.03, 60.23) (TD patients with iron chelation therapy) NR NR‡ Yang et al. ASCO Ann meeting. 2016;e18556–e18556. Marketscan 1,658 NR NR Proportion of patients with RBC transfusion by line of therapy 13% (no therapy)25% (first-line therapy)32% (second-line therapy)35% (third-line therapy) NR All patients treated with ruxolitinib Pemmaraju et al. ASCO Ann meeting. 2020;e19535–e19535. Cardinal Health (chart review) 26 NR NR NR NR NR NR‡ Gimenez et al. J Med Econ. 2014;17:435–41. Three hospitals in Spain 33 NR NR Proportion of patients who needed transfusion Among splenomegaly symptomatic patients:33% (patients with constitutional symptoms and anemia)0% (patients with constitutional symptoms without anemia)21% (patients without constitutional symptoms with anemia)0% (patients without constitutional symptoms and anemia) Among splenomegaly asymptomatic patients:16% (patients with constitutional symptoms and anemia)2% (patients with constitutional symptoms without anemia)32% (patients without constitutional symptoms with anemia)0% (patients without constitutional symptoms and anemia) NR NR‡ Pastor-Galan et al. Med Clin. 2020;155:152–8. Spanish Registry of Myelofibrosis (GEM-MIE-2014-01) 1,000 Proportion of patients with anemia 36% NR NR NR All patients treated with ruxolitinib Palandri et al. Hematol Oncol.202;38:372–80. European Hematology centers 589 NR NR NR NR NR All patients treated with ruxolitinib Breccia et al. Ann Hematol. 2019;98:889–96. European Hematology centers 462 Proportion of patients with ruxolitinib inducted anemia 76% (any grade, any time)67% (any grade, at month 3)53% (any grade, at month 3) NR NR NR All patients treated with ruxolitinib Palandri et al. Br J Haematol. 2018;183:35–46. European Hematology centers 291 Proportion of patients developed anemia of any grade during ruxolitinib therapy 93 3% NR NR NR All patients treated with ruxolitinib Palandri et al. Oncotarget. 2017;8:79073. European Hematology centers 408 NR NR NR NR NR All patients treated with ruxolitinib Palandri et al. Cancer. 2020;126:1243–52. European Hematology centers 268 Proportion of patients with anemia (hemoglobin <10 g/dL) 51.5% (at the start of ruxolitinib)69.9% (at discontinuation of ruxolitinib) NR NR NR All patients treated with ruxolitinib Palandri et al. Hematol Oncol. 2018 Feb;36:285–90. European Hematology centers 70 Proportion of patients with ruxolitinib-induced anemia 45.7% Proportion of patients requiring occasional transfusion support 21.4% NR Proportion of patients acquired TD during ruxolitinib treatment 4.3% All patients treated with ruxolitinib Mazza et al. Leuk Lymphoma. 2017;58:138–44. Six institutions from the Apulia region in the south of Italy 65 Proportion of patients with mild anemia during ruxolitinib treatment 5% Proportion of patients who needed RBC transfusion 23% (before ruxolitinib)37% (during ruxolitinib)15% (after ruxolitinib) NR All patients treated with ruxolitinib Breccia et al.Ann Hematol. 2019;98:1933–6. Nine Italian hematological centers 53 Proportion of patients with grade 2 or above anemia during ruxolitinib treatment 45% NR NR NR All patients treated with ruxolitinib Breccia et al.Ann. Hematol. 2017;96:387–91. Nine Italian hematological centers 98 Proportion of patients experienced anemia of any grade 39.7% NR NR NR NR‡ Guglielmelli et al. Am J Hematol. 2016;91:918–922. Six Italian centers of the AGIMM consortium 490 Proportion of patients with anemia stratified by fibrosis grade 28.0% (overall)17.2% (grade 1 fibrosis)29.1% (grade 2 fibrosis)43.0% (grade 3 fibrosis) NR NR NR NR‡ Caocci et al. Int J Hematol. 2020;111:614–8. One Italian medical center 106 NR NR Median number of RBC units received 24 (TD patients with infection complication)15 (TD patients without infection complication) NR NR‡ Beauverd et al. Br J Haematol. 2016;175:37–42. Guy’s and St Thomas’ NHS Foundation Trust (UK) 43 Proportion of patients with anemia (hemoglobin < 10 g/dL) at referral 7.5% Proportion of patients with TD at referral 7% NR Proportion of patients who developed anemia during follow-up 17.6% All patients treated with ruxolitinib Barraco et al. Br J Haematol. 2020;191:764–74. The PASS (post-authorization safety study) study 259 Treatment-emergent anemia per 100 patient-years 3.8 NR NR NR *Randomized controlled trial included in network meta-analysis by Sureau et al.7†Only patients who completed at least 22 weeks of follow-up after randomization and before clinical hold were considered.‡Treatment information was not extracted for real-world studies where patients used various types of treatment or where treatment use was not reported.BAT = best available therapy; BID = twice per day; BL = baseline; JAKi = Janus kinase inhibitor; MF = myelofibrosis; NR = not reported; PET = postessential thrombocythemia; PMF = primary myelofibrosis; PPV = postpolycythemia vera; QD = once per day; RBC = red blood cell; TD = transfusion dependent; TI = transfusion independent; UK = United Kingdom; W = week. To address this, we conducted an expanded targeted literature review within the MEDLINE, Embase, Cochrane, NHS Economic Evaluation, and Health Technology Assessment databases to identify articles published between January 2011 and February 2021 reporting treatment outcomes of phase 2 and phase 3 clinical trials and real-world studies in MF in the United States, United Kingdom, France, Germany, Italy, or Spain, with at least 25 patients per arm or cohort. Both approved (ie, ruxolitinib, fedratinib, pacritinib) and investigational (ie, momelotinib, as well as the telomerase inhibitor imetelstat and the transforming growth factor beta trap luspatercept) MF treatments were assessed. A total of 52 publications were identified, including 29 real-world studies and 23 records covering 16 clinical trials (Table 1). No published study of luspatercept met the inclusion criteria. A detailed review of the 15 clinical trial publications that reported anemia- or transfusion-related outcomes in MF confirmed that momelotinib not only had the lowest grade 3/4 anemia rates among JAKi but also showed the greatest improvement in transfusion independence rates (Table 1). Specifically, reported rates of treatment-emergent grade 3/4 anemia ranged from 6% to 14% for momelotinib, 20% to 42% for ruxolitinib, 38% to 60% for fedratinib, 7% to 27% for pacritinib, and 30% for imetelstat. Overall, the proportion of transfusion-independent patients from baseline to week 24 or end of the treatment period decreased by 13% to 21% for ruxolitinib, decreased by 9% for fedratinib, remained stable with a 1% increase for pacritinib, and ranged from a 2% decrease to a 12% increase for momelotinib. Notably, momelotinib-treated patients experienced a higher rate of transfusion independence at week 24 compared with those treated with ruxolitinib in the head-to-head phase 3 SIMPLIFY-1 trial (66.5% versus 49.3%, nominal P < 0.001) and those treated with best available therapy (88.5% ruxolitinib) in SIMPLIFY-2 (43% versus 21%, nominal P = 0.0012).8,9 Further, momelotinib-treated patients experienced lower rates of transfusion dependence at week 24 than ruxolitinib-treated patients in SIMPLIFY-1 (30.2% versus 40.1%, nominal P = 0.019), where the median rate of transfusion was 0 units/month with momelotinib compared with 0.4 units/months with ruxolitinib (nominal P < 0.001).8 Our targeted literature review also identified a growing body of real-world evidence demonstrating the substantial clinical burden associated with anemia and transfusions among patients with MF. Specifically, we identified 29 real-world reports of anemia- and transfusion-related outcomes (Table 1), including 14 studies conducted in the US (9 single-center studies, 3 database analyses, and 2 chart reviews), 14 conducted in Europe (11 multicenter, 2 single-center, and 1 registry study), and 1 conducted globally (multicenter registry study). Rates of anemia and transfusion dependence varied widely across the 24 real-world studies that directly reported it; among these MF populations, 5% to 93.3% of patients were anemic and 7% to 62% were transfusion dependent. Reported rates of ruxolitinib treatment modification due to anemia ranged from 8% to 36%, and rates of ruxolitinib discontinuation due to anemia ranged from 5% to 33%. Additionally, we identified 5 real-world studies and 1 pooled clinical trial analysis that evaluated the association between anemia and overall survival in patients with MF, which include a range of treatments (Table 2). Among these, 5 of the 6 studies demonstrated an association between anemia and shortened overall survival (univariate hazard ratio range: 1.20–3.28; multivariate hazard ratio range: 1.27–1.92), and a similar trend was observed in the sixth study (Table 2), consistent with the known negative prognostic value of anemia in MF.3 Table 2 - Summary of the Impact of Anemia on Overall Survival in Clinical and Real-world Studies of MF Publication Study Description Treatment Anemia Rate Hazard Ratio of Anemia vs Nonanemia(95% CI), P Univariate Analysis Multivariate Analysis Guglielmelli et al. Am J Hematol. 2016;91:918–922. This study used 490 PMF patients with fibrosis grade ≥ 1 from 6 Italian centers of the AGIMM consortium to analyze the prognostic impact of fibrosis grade. Prognostic impacts of other clinical, hematological, and molecular variables were also reported. NR 28% 3.28 (2.39–4.49), P < 0.0001 1.89 (1.33–2.70), P < 0.0001 Masarova et al. Leuk Res.2017;59:110–116. This study used 1,099 patients with PMF, PET/MF, or PPV/MF who were referred to the University of Texas MD Anderson Cancer Center between 1984 and 2013 to assess and compare the biologic, clinical, and prognostic features of PMF, PET/MF, and PPV/MF patients. Hydroxyurea, ruxolitinib, stem cell transplantation, no treatment, investigational treatment, etc. 43% (PMF)41% (PET/MF)38% (PPV/MF) PMF:1.2 (1.02–1.5), P = 0.03 PET/MF:1.9 (1.19–3.10), P = 0.007 PPV/MF:1.75 (1.17–2.63), P = 0.007 PMF:1.27 (1.02–1.58), P = 0.031 PET/MF:Not statistically significant PPV/MF:1.81 (1.17–2.78), P = 0.008 Palandri et al. Cancer. 2020;126:1243–1252. This study investigated 268 patients who discontinued ruxolitinib between June 2011 to October 2018 from a multicenter (consisting of 20 European hematology centers) observational retrospective study. The study investigated reasons for discontinuation and impact on outcomes (e.g., overall survival). Ruxolitinib 69.9% after discontinuation of ruxolitinib 1.70 (1.05–2.76), P = 0.03 1.92 (1.19–3.11), P = 0.01 Szuber et al. Am J Hematol. 2018;93:1474–1484. This study investigated 3,023 patients with myelofibrosis who were seen at MayoClinic between 1967 and 2017. The study assessed the natural history, prognostic markers, and long-term outcomes among these patients. NR 47% 2.6 (0.84–7.2), P = 0.09 NR Tefferi et al. Mayo Clin Proc. 2012;87:25–33. This study assessed 1,000 patients with PMF who were seen at Mayo Clinic between 1977 and 2011. This study (1) reported clinical and laboratory features for both patients seen at time of diagnosis and those seen at different time points from diagnosis, (2) presented the natural history of the disease, including overall and leukemia-free survival, in the context of contemporary prognostic scoring systems, and (3) assessed the prognostic impact of relevant risk factors. Allogeneic stem cell transplant, ruxolitinib, pomalidomide, etc. 54% 2.4 (2.1–2.9), P < 0.001 1.6 (1.3–2.1), P < 0.001 Verstovsek et al. J Hematol Oncol. 2017;10:156. This study analyzed the long-term survival in patients treated with ruxolitinib for myelofibrosis using the 5-year data pooled from the COMFORT 1 and COMFORT II trials. Ruxolitinib or placebo (COMFORT I)Ruxolitinib or BAT (COMFORT II) 45.8% (ruxolitinib)49.8% (control) Ruxolitinib arm: 2.70 (1.64, 4.44)Placebo arm:1.51 (0.92, 2.34) NR BAT = best available therapy; CI = confidence interval; MF = myelofibrosis; NR = not reported; PET = postessential thrombocythemia; PMF = primary myelofibrosis; PPV = postpolycythemia vera. Although the substantial clinical burden associated with anemia and transfusion dependence has been well documented in patients with MF, our review sought to quantify the impact of anemia and transfusions on HRQoL and economic outcomes in this specific patient population. Overall, we found that data from adequately sized MF patient populations is lacking in these areas. An investigation from the Nordic MPN Study Group found that transfusion-dependent patients with MF had significantly worse QoL scores than nontransfusion dependent patients; however, this study did not meet our review inclusion criteria for sample size per cohort, and it did not address economic implications.10 In patients with myelodysplastic syndromes, myeloid neoplasms with many features in common with MF including anemia, transfusion burden is associated with significant HRQoL and economic burden, with transfusion-dependent patients incurring 53% higher total costs over 2 years.11 Future investigation is needed to quantify the full HRQoL and economic impact attributable to anemia and transfusion dependence in MF to assess the true value of current therapies as well as emerging treatments that have the potential to address all key hallmarks of MF, including anemia, splenomegaly, and symptoms. Consistent with findings from Sureau et al,7 our expanded targeted literature review corroborates the inadequacy of ruxolitinib in addressing the unmet need among anemic patients with MF in real-world clinical practice. Anemic MF patients receiving ruxolitinib may require dose reductions, treatment interruptions, or early treatment discontinuation, which can reduce treatment efficacy, or red blood cell transfusions throughout the course of therapy. Furthermore, nearly 50% of MF patients treated with ruxolitinib require add-on agents to treat anemia, such as androgens, corticosteroids, or erythropoiesis-stimulating agents.12 Despite the use of supportive measures, the median duration of ruxolitinib treatment in the real-world setting is shorter than in clinical trials.13 While the reasons for this short duration of treatment may be multifaceted, evidence suggests that adverse events (including anemia) and loss of treatment response are important contributing factors.13 The emergence of treatment options that directly address anemia in addition to the other key hallmarks of MF may lead to improved patient outcomes. Momelotinib inhibition of ACVR1/ALK2 in addition to JAK1 and JAK2 leads to decreased hepcidin, the master regulator of iron metabolism that is elevated in MF patients, and subsequent increased serum iron availability for erythropoiesis.14 Momelotinib may be a valuable first- or second-line JAKi option for anemic patients with MF, as its ability to reduce rates of anemia and transfusion dependence in addition to spleen volume and symptoms has been demonstrated in phase 3 trials and further confirmed by Sureau et al.7 In addition, several combination therapies are in advanced clinical development that have demonstrated clinical activity against anemia and other key hallmarks of MF, including ruxolitinib plus luspatercept, an activin receptor IIB ligand trap/erythroid maturation agent, ruxolitinib plus pelabresib, a bromodomain and extra-terminal protein (BET) inhibitor, and ruxolitinib plus navitoclax, a antiapoptotic B-cell lymphoma protein (BCL-XL, BCL-2, BCL-w) inhibitor.15 Studies to address the substantial evidence gap identified in our targeted literature review surrounding quantification of the HRQoL and economic burden of anemia and transfusions in MF will be imperative to assessing therapeutic value among the growing number of currently available and new agents entering the MF treatment landscape. AUTHOR CONTRIBUTIONS JS and BK designed the study. JS conducted the search. ATG, PB, GH, AK, LMN, JS, BK, and CH analyzed the data and interpreted the findings. LMN wrote and edited the manuscript with input from ATG, PB, GH, AK, JS, BK, and CH. DISCLOSURES Aaron T. Gerds has served as a consultant for Celgene/Bristol Myers Squibb, Pfizer, Kartos Therapeutics, Promedior, and CTI BioPharma; Prithviraj Bose has received research support from Incyte, Bristol Myers Squibb, CTI BioPharma, Constellation/Morphosys, Kartos, Blueprint Medicines, Cogent, Pfizer, Astellas, NS Pharma and Promedior, and honoraria from Incyte, Bristol Myers Squibb, CTI BioPharma, Sierra Oncology, Abbvie, Constellation/Morphosys, Karyopharm, Pharma Essentia, Blueprint Medicines and Novartis; Gabriela S. Hobbs served as a consultant for Celgene/Bristol Myers Squibb, Pfizer, Blueprint Medicines, Incyte, Novartis, Abbvie, Keros and Pharmaxis; Andrew T. Kuykendall has received clinical research funding from Sierra Oncology, Constellation/Morphosys, and Celgene/Bristol Myers Squibb and has served on advisory boards for CTI Biopharma, Novartis, Abbvie, Celgene/Bristol Myers Squibb, Constellation/Morphosys, and Imago Biosciences; Lynn M. Neilson and Barbara Klencke are employees of Sierra Oncology; Jinlin Song is an employee of Analysis Group; and Claire Harrison has received clinical research funding from Novartis, Constellation, and Bristol Myers Squibb, and has served on advisory boards and as a speaker for Novartis, Celgene/Bristol Myers Squibb, CTI BioPharma, Gilead Sciences, Shire, Roche, Janssen, Promedior, Geron, AOP, Galecto, Sierra Oncology, Constellation, and Keros, and is Deputy Editor in Chief of HemaSphere. SOURCES OF FUNDING Momelotinib is sponsored by Sierra Oncology. The targeted literature search was performed by Analysis Group, which was sponsored by Sierra Oncology. DATA AVAILABILITY STATEMENT All data generated or analyzed during this study are included in this published article.